Maternal smoking during pregnancy causes a broad range of effects on the developing lung of the fetus that greatly impairs its long-term function and capacity. The molecular mechanisms underlying these effects are not known. Since both normal lung development and injury/repair utilize common alveolar epithelial-mesenchymal signaling pathways to maintain homeostasis, we propose that in utero nicotine exposure disrupts the critical homeostatic epithelial-mesenchymal paracrine signaling pathways, resulting in the transdifferentiation of alveolar intersitial fibroblasts (AIFs) to myofibroblasts (MYFs). This AIF-to-MYF transdifferentiation is characterized by down regulation of the Peroxisome Proliferator Activated Receptor gamma (PPAR() signaling pathway and up regulation of the Wingless/Int (Wnt) signaling pathway. Although the effects of in utero nicotine exposure on PPAR( signaling have recently been described, there is no information on its effect on the Wnt signaling in the developing lung. We hypothesize that in utero nicotine exposure up-regulates AIF Wnt signaling and that by specific molecular targeting to down regulate the Wnt signaling and/or up regulate the PPAR( signaling, in utero nicotine-induced lung injury can be prevented or even reversed. Using well established in vitro and in vivo models of in utero nicotine-induced lung injury, through real-time RT- PCR, Western analysis, immunohistochemistry, laser capture microdissection, metabolomics, antisense and over expression studies, and in vivo pulmonary function tests, we will determine (1) how in utero nicotine exposure alters lung development, resulting in altered structure and function, and (2) if PPAR( agonists and/or Wnt antagonists, either alone or in combination, can prevent and/or reverse perinatal nicotine exposure-induced alterations in PPAR( and Wnt signaling in lung mesenchyme, and hence lung structure and function. Since the paradigm and models used by us are based on a universal developmental model for the formation, establishment, and homeostasis of the alveolar acinus, the information generated will not be limited only to in utero nicotine-induced injury but is likely to have a much larger applicability to lung development and injury/repair in general. Therefore, by utilizing functional genomics, the studies proposed herein are likely to translate into novel and innovative molecular preventive and therapeutic approaches for all chronic lung diseases in general. PROJECT NARRATIVE: Maternal smoking during pregnancy poses significant risks not only during gestation and immediate newborn period, but may also results in life long medical complications including devastating respiratory problems. The mechanisms underlying the harmful effects of maternal smoking on the lung are complex and incompletely understood. Using novel and innovative concepts, and the state-of-the-art technology, the proposed studies will unravel mechanisms that underlie not only the in utero smoke exposure-induced lung injury, but also almost all other forms of chronic lung diseases.